Pathogenesis of the Metabolic Syndrome: Insights from Monogenic Disorders

Table 1

Summary of lessons learned from monogenic disorders resulting in nonsyndromic obesity, pancreatic beta cell diabetes, and severe insulin resistance.

	Lessons	Human examples	References
1	Proof that humans can become obese as a result of single-gene defects controlling key central components of appetite	Several etiologies of severe human obesity result from single genes involved in appetite pathways for example, LEP, LEPR, POMC, MC4R, BDNF, TrkB	[1–6]
2	Genetically mediated differences in satiety are likely to underly the difference in body weight seen in the current obesogenic environment	Several common single-nucleotide polymorphisms involving similar appetite components for example, MC4R and BDNF have been identified at greater frequency in those with common obesity	[7, 8]
3	Proof of key components of pancreatic beta cell function and responsiveness of certain genetic etiologies to oral glucose lowering drugs acting distal to the monogenic defect	Those with mutations in KCNJ11, ABCC8, HNF1A, HNF4A are able to be treated with sulphonylurea tablets rather than insulin, given that their molecular defects are upstream of the SUR1 receptor where sulphonylureas act to promote insulin secretion	[9]
4	Glucose toxicity is not seen in those with lifelong, mild hyperglycaemia resulting from a heterozygous glucokinase mutation	Those with heterozygous GCK mutations have stable, mild hyperglycaemia with no deterioration in beta cell function with age	[10]
5	Exposure to mild hyperglycaemia in utero does not program non-mutation carrying offspring to have reduced beta cell function	Non-mutation carrying offspring born to mothers with GCK who have experienced mild hyperglycaemia in utero do not have reduced beta cell function compared to those born to fathers with GCK	[11]
6	Pancreatic beta cell defects in type 2 diabetes are likely to be multifocal including sites distal to the SUR1 receptor where sulphonylureas act to promote insulin secretion	The progressive failure of sulphonylurea therapy in those with type 2 diabetes compared to durable response seen in monogenic causes upstream of SUR1 receptor	[12]
7	Insulin receptor signaling on pancreatic islets is not required for beta cell compensatory response to severe insulin resistance	Those with a global defect in their insulin receptor due to INSR mutations have dramatically high levels of circulating insulin	[13]
8	Acanthosis nigricans and ovarian hyperandrogenism are likely to be mediated by hyperinsulinemia acting through non-insulin receptor pathways	Those with a global defect in their insulin receptor due to INSR mutations have marked acanthosis nigricans and such women have ovarian hyperandrogenism	[14]
9	Development of fatty liver and dyslipidemia are dependent on adequate insulin-receptor signalling	Those with a global defect in their insulin receptor due to INSR mutations do not develop fatty liver or dyslipidemia, despite markedly elevated levels of circulating insulin	[15]
10	Selective postreceptor (partial) hepatic insulin resistance occurs in common metabolic dyslipidemia rather than total postreceptor insulin resistance	Fatty liver and dyslipidemia frequently coexist with common metabolic syndrome insulin resistance	[15]
11	Not all fat is bad	Those with inherited defects in fat metabolism resulting in partial or complete loss of body fat have exaggerated dyslipidemia, fatty liver, and insulin resistance	[16]